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Wednesday, July 10, 2013

Irwin McLean's filaggrin readthrough drug could be revolutionary

Recently I predicted that nothing resembling a cure for eczema would appear for at least 25 years. I followed that up with a prediction that if a surprise cure were to emerge, it would be an anti-itch therapy.

At least one reader disagreed, and pointed me to a strategy now being developed at the University of Dundee in Scotland: drugs to stimulate or enable filaggrin expression in patients with one or two defective copies of the corresponding gene, FLG. At least one such drug is in the very earliest stages of drug development, toxicology studies in animals. If the drug succeeds in human clinical trials, we might see it in clinics in about 15 years. Potentially, such a drug could help some of the patients most severely affected by eczema.

The best review on filaggrin I’ve seen was co-written by three authors, two of whose names I am familiar with as among the biggest in the field of eczema research: Irwin McLean, who led the team that linked mutations in FLG to increased risk of developing ichthyosis vulgaris and eczema, and Donald Leung, principal investigator of the Atopic Dermatitis Research Network. (The first author is Alan Irvine, a colleague of McLean’s who works in Ireland.)

FLG is a giant, and unusual, gene, one of the last to be sequenced by the Human Genome Project. It encodes an enormous protein, profilaggrin, which contains from 10 to 12 repeats that are cleaved off into individual filaggrin units. Filaggrin itself has several important roles in the upper layers of the skin: it flattens skin cells into their characteristic final shape; it helps bind these cells together into a barrier; and it breaks down into the acidic “natural moisturizing factor.”

Many mutations have been found in FLG. Interestingly, if you take any particular ethnic group (say Japanese), there will be a characteristic profile of mutations for this group that is likely to be different than the profile for another group (say Scottish).

FLG (read from left to right; red hexagons are filaggrin units.) Common
mutations in Asian and European populations. Look how early the nonsense mutation
R501X appears. Figure 3A from Irvine, McLean, and Leung's NEJM review

All filaggrin variants are either “nonsense” or “frameshift” mutations in DNA that encodes protein (as opposed to so-called “junk DNA”). In a nonsense mutation, the correct DNA base has been replaced with a wrong one, and the upshot is that the protein-making machinery, known as the ribosome, runs into a code that it doesn’t recognize; it can’t add an amino acid to the growing protein, and it stops decoding profilaggrin at that point.

If the nonsense mutation occurs early enough, before the first filaggrin unit in FLG, no filaggrin gets made at all.

I believe that with a frameshift mutation (in which one or more DNA bases are missing or added) the protein is very likely to be terminated soon afterward. The end result is the same: little or no filaggrin.

In his 2006 Nature Genetics paper, McLean and his group identified two mutations, R501X (nonsense) and 2282del4 (frameshift), which have turned out to be the most common in Caucasian populations. Both R501X and 2282del4 occur early in the first filaggrin repeat. That means that if you have one such mutation, you will have one good copy of FLG and one bad copy; and if you have mutations on both your copies of FLG, you won’t have any filaggrin at all, and there is a high chance that you have eczema.

Soon after their 2006 discovery, McLean and first author Frances Smith applied for a US patent, “Prevention/treatment of ichthyosis vulgaris, atopy and other disorders.” The patent, number 8,338,386, was granted only recently, on December 25, 2012. It makes many claims, all relating to the ability of five antibiotic drugs, or potentially tRNA molecules, to force the ribosome to read through nonsense mutations.

McLean and Smith’s patent is aimed at the nonsense mutation R501X (they say so in the patent), because it occurs so early in the gene. Such a drug would also work for nonsense mutations later in the sequence.

The drug or agent would not work on frameshift mutations such as 2282del4, as I understand it.

One cool thing about a readthrough drug would be that it would have its strongest effect on people who had nonsense mutations on both copies of FLG. A readthrough drug would theoretically make both copies functional. People with only one mutated copy of FLG would still benefit from having that number increased to two.

In the patent,“atopy” is mentioned in the title and the background information, but neither “atopy” nor “atopic dermatitis” appear in any of the 14 explicit claims. I don’t know whether this matters. I'm not an IP lawyer. It seems curious that the inventors left it out though.

Another curious fact is that only five specific drugs are mentioned: gentamicin, paromomycin, neomycin, tobramycin and negamycin. There is no discussion of the drug discovery process—any tweaking of molecules for greater effect or less toxicity—that I can see. I don’t know whether this matters either.

From what I can tell, McLean’s group has at least one of these compounds, which has most likely been altered from its original structure, in “toxicology” (which means testing in mice, rats, etc.) (see page 16). If you look at this handy graphic provided by the FDA, you will see that toxicology studies are step 2 of 12 in the drug discovery-to-market process. So it is extremely early days and you have to keep in mind that, as I keep saying, almost all drug candidates fail at some stage of clinical testing.

A relevant factor is also that currently there is no FDA-approved drug that acts by this mechanism—by causing the ribosome to ignore nonsense mutations. Ataluren, a drug to cure Duchenne muscular dystrophy and cystic fibrosis, is a readthrough drug in phase III clinical trials. The FDA is apparently especially careful when approving drugs that are “first-in-class,” or the first of their general type. So it is worth following Ataluren’s progress closely; its success could mean that we might see an eczema readthrough drug sooner.

12 comments:

I´ve been thinking a little bit of the fact that they don´t mention the word "dermatitis" or "eczema" in the patent application.

When they were searching for mutations in filaggrin, they studied individuals with Ichthyosis Vulgaris, not AD. I bet they wrote the claims before they were able to prove the high prevalence of FLG mutation in AD. At that time, the inside-out hypothesis was the dominating one in AD research, and this research changed that paradigm. Now the outside-in hypothesis is dominating. I think they found that a potential cure for IV was reason "good enough" to file the patent application, and wanted to do before anybody else did so. Mind you, the FLG/IV paper was published earlier than the FLG/AD paper(s). They also mention psoriasis in the patent application, but this disease has been proven not to be more common in FLG individuals. So, the patent is based onwhat they KNEW and were able to prove at that time, and it also holds some elements of speculation. Some of those speculations have been proven right (AD), and some have been proven wrong. (psoriasis).

This is just a theory from my side...

Regarding the use of aminoglycoside antibiotics: As far as I can see, the patent covers the use of any drug with read-through effect. I do believe that their intention is only to exhibit some early stage "proof of concept", and of course, they had to do this by using drugs avialable at that time. (Gentamicin, negamycin etc..)

You would think that McLean would have filed another patent explicitly for this technique in AD. He appears not to have.

However, if you search patent APPLICATIONS (as opposed to patents granted) you find another listing which covers FLG mutations as diagnostics for infants developing AD--and also gene therapy for FLG mutation. IMO it's pretty bold of him to pack those two concepts into a single patent!

I dunno. If I were a competing scientist at big pharma, I might find that wording vulnerable. I'd think it would be best to be as specific as possible. I mean, look at the detail they go into in the individual claims.

And btw, I wouldn´t say that the FDA graphic shows the drug discovery process. In my (and FDA´s) opinion, it shows the drug approval process. Drug discovery is basically done in step one, and maybe step two, in the FDA graphic. Of course, the graphic illustrates your point brilliantly, and the clinical trials and the approval processes are extremely time consuming,but I would say that this figure illustrates drug discovery process itself better: (check out what´s the last step!)http://www.celgene.com/research/drug-discovery-and-development.aspx

Agreed. I bet there has been a lot of "move one step back". But I believe/hope that they have done their work properly. AD/IV/atopy patients are one h*ll of a powerful group, and skin disease patients have always been "itching" for a cure. And this discovery of the first genetic predisposing factor for AD has indeed triggered a lot of media interest. Thus, I don´t think they would move in to trials in humans if they not were confident that their compound(s) might work. The media coverage has been too comprehensive, the patient group is "too big to disappoint", (if you catch my drift), and the related diseases are not life threatening, so I don't think that time ha been an issue. In my mind, they are working to develop a high quality product that not necessarily has to enter market "tomorrow".

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